Mouse Models And LRRK2 Kinase Substrates for Park8-Parkinson's Disease

Park8-帕金森病的小鼠模型和 LRRK2 激酶底物

• 批准号: 7273867
• 负责人: CHENJIAN LI
• 金额: $ 18.35万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273867
• 关键词: Address; Bacterial Artificial Chromosomes; Behavioral; Cessation of life; Detection; Development; Disease; Dopamine; Dopaminergic Cell; Exploratory/Developmental Grant; Figs - dietary; Functional disorder; Future; Gene Transfer Techniques; Genes; Genetic; Human; Hyperactive behavior; Knock-out; LRRK2 gene; Lead; Left; Leucine-Rich Repeat; Mediating; Methods; Missense Mutation; Modeling; Molecular; Motor; Mus; Mutation; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Population Study; Prevalence; Production; Protein Overexpression; Proteins; Research; Role; Signal Transduction; Substantia nigra structure; Testing; Therapeutic; Therapeutic Studies; Transgenic Mice; Transgenic Organisms; dopaminergic neuron; drug testing; early onset; gain of function; leucine-rich repeat kinase 2; motor deficit; mouse model; mutant; neurochemistry; pars compacta; therapeutic target; tool

DESCRIPTION (provided by applicant): The newly identified LRRK2, a disease gene of familial dominant late-onset ParkS, encodes a kinase. No mouse models are available for ParkS; no LRRK2 kinase substrates are known; and little is known about LRRK2 normal functions and pathogenic roles in Parkinson's disease. In this early exploratory phase of research which is most suitable for R21 mechanism, we have established LRRK2 mouse models and now propose to characterize them, and utilize these new mouse models to identify LRRK2 substrates. Mutations in LRRK2 have been identified as the most prevalent ones in familial Parkinson's disease, as well as in sporadic PD unexpectedly. All ParkS mutations are missense mutations that cause a dominant phenotype, indicating a "gain of function" or "hyperactivity" mechanism of mutant proteins for pathogenesis. Therefore, transgenic (not knockout) mouse models are appropriate for modeling ParkS. Our CENTRAL HYPOTHESIS is that ParkS pathology is caused by hyperactivity of the mutant LRRK2 to hyper-phosphorylate its substrates. To test this hypothesis, we have generated transgenic LRRK2 mice that carry wild type sequence or ParkS mutations in HUMAN bacterial artificial chromosome (BAG). SPECIFIC AIM 1: to analyze the phenotypes of the LRRK2 transgenic mice for progressive behavioral deficits in motor function and in niagrostriatal pathways, neuronal pathology in substantia nigra, and dopamine production and release. SPECIFIC AIM 2: to use our new mouse models to identify substrates of LRRK2 kinase with both candidate and non-biased approaches. SIGNIFICANCE: Mouse models for ParkS will be critical tools for mechanistic studies and future therapeutic drug testing. The identification of LRRK2 substrates is important because kinase pathways and components are highly "drug-able" targets. The study of LRRK2 is also very likely to impact sporadic PD research, because ParkS mutation G2019S was discovered to be also highly prevalent in sporadic PD.

描述（由申请人提供）：新发现的LRRK2是家族显性晚发性ParkS的疾病基因，编码一种激酶。没有小鼠模型可用于ParkS；没有已知的LRRK2激酶底物；LRRK2在帕金森病中的正常功能和致病作用知之甚少。在这个最适合R21机制的早期探索阶段，我们已经建立了LRRK2小鼠模型，现在打算对其进行表征，并利用这些新的小鼠模型来鉴定LRRK2底物。LRRK2突变已被确定为家族性帕金森病中最普遍的突变，并且意外地在散发性帕金森病中也是如此。所有的ParkS突变都是引起显性表型的错义突变，表明突变蛋白的发病机制是“功能获得”或“多活性”机制。因此，转基因（非基因敲除）小鼠模型适合用于建模ParkS。我们的中心假设是，ParkS病理是由突变体LRRK2的过度活性导致其底物过度磷酸化引起的。为了验证这一假设，我们培育了携带人类细菌人工染色体（BAG）野生型序列或ParkS突变的转基因LRRK2小鼠。具体目的1：分析LRRK2转基因小鼠在运动功能和谷纹状体通路进行性行为缺陷、黑质神经元病理以及多巴胺产生和释放方面的表型。具体目标2：使用我们的新小鼠模型，用候选和非偏倚方法鉴定LRRK2激酶的底物。意义：小鼠模型将成为机制研究和未来治疗性药物测试的重要工具。LRRK2底物的鉴定很重要，因为激酶途径和成分是高度“可药物”的靶标。LRRK2的研究也很有可能影响散发性PD的研究，因为ParkS突变G2019S也被发现在散发性PD中高度流行。